The mammalian immune system uses two general adaptive mechanisms to protect the body against environmental pathogens. One is the non-specific (or innate) inflammatory response. The other is the specific or acquired (or adaptive) immune response. Innate responses are fundamentally the same for each injury. In contrast, acquired responses are custom tailored to the pathogen.
The immune system recognizes and responds to structural differences between self and non-self proteins. Proteins that the immune system recognizes as non-self are called xe2x80x9cantigensxe2x80x9d. Pathogens express large numbers of highly complex antigens. Acquired immunity has specific xe2x80x9cmemoryxe2x80x9d for antigenic structures, and repeated exposure to the same antigen increases the response, which increases the level of induced protection against that particular pathogen.
Acquired immunity is mediated by specialized immune cells called B and T lymphocytes. B lymphocytes produce and mediate their functions through the actions of antibodies. B lymphocyte dependent immune responses are referred to as xe2x80x9chumoral immunityxe2x80x9d because antibodies are detected in body fluids. T lymphocyte dependent immune responses are referred to as xe2x80x9ccell mediated immunityxe2x80x9d because effector activities are mediated directly by the local actions of effector T lymphocytes. The local actions of effector T lymphocytes are amplified through synergistic interactions between T lymphocytes and secondary effector cells, such as activated macrophages. The result is that the pathogen is killed and thereby prevented from causing disease.
Cancer immunity is mediated exclusively by T lymphocytes, which means that it involves acquired cell mediated immunity and does not involve B lymphocytes or antibodies. An activated acquired immune response kills cancer cells and rejects the cancer.
Medical interventions often make use of the fact that acquired immune responses can be artificially manipulated. Exposing individuals to a weakened pathogen induces acquired immunity without causing disease and protects the individual against later exposure to the same pathogen. The general process of artificially inducing protective immune responses is called vaccination. Protective immunity to some pathogenic agents can be transferred from one individual to another using T lymphocytes. Although cancer immunity can be transferred between individuals using T lymphocytes, currently there are no accepted medical interventions that employ T lymphocyte transfer between individuals.
Vaccines are mainly useful for disease prevention. Vaccination has been used to induce protection against a wide variety of environmental pathogens, particularly viruses. The dramatic success that has been achieved with vaccines has led to a search for therapeutic applications. The search for a therapeutic AIDS vaccine is one well-known example. Unfortunately, manipulating the immune system to treat pre-existing disease has proven much more difficult than manipulating the immune system for protection. The only well-documented success against human disease has been achieved in rabies. Multiple vaccinations can prevent rabies from developing after exposure to the virus. The same general rationale has been applied to cancer treatment. The thought has been that, since, unlike viruses, cancers are relatively slow growing, it could be possible to use vaccines to slow or prevent further growth or spread. However, only very limited success has been achieved with cancer vaccines.
It is not intuitive that malignancies would be susceptible to immune manipulation. Malignant cells are genetically altered normal cells, not foreign pathogens. The immune system must be able to recognize malignant cells as non-self, and it must be possible to manipulate the immune system to reject cancer cells that may have spread to remote body sites. Although malignant cells are not actually foreign pathogens, there is widespread agreement that malignant cells can be recognized as non-self Cancer antigens are generated from the genetic changes that cancer cells go through during malignant transformation and progression. See Srivastava, Do Human Cancers Express Shared Protective Antigens? Or the Necessity of Remembrance of Things Past, Semnin. Immunol. 8:295-302 (1996). However, the extent to which the immune system of patients with progressing cancers can be manipulated is extremely controversial. See Ellem et al., The Labyrinthine Ways of Cancer Immunotherapyxe2x80x94T Cell, Tumor Cell Encounter: xe2x80x9cHow Do I Lose The? Let Me Count The Ways,xe2x80x9d Adv. Canc. Res. 75:203-249 (1998). This is mainly due to the fact that, like attempts to use the immune system to treat infectious disease, attempts to manipulate the immune system for the therapeutic benefit of cancer patients have been largely unsuccessful. Controversy about the potential susceptibility of human cancer to immune manipulation also arises from the fact that it is widely believed that human malignancies are weakly immunogenic. Consequently, there have been very few systematic attempts to determine the relative immunogenicity of human cancers.
How do researchers determine whether a substance is antigenic or that an acquired immune response has been induced in an individual that has been exposed to an antigen? For humoral immunity, there is a myriad of in vitro assays for measuring an increase in serum antibody levels. It is infinitely more difficult, however, to determine that a cell mediated immune response has been induced. Over the years, in vivo protection assays have proven to be the most reliable indicators when the antigen is a pathogen. Protection assays work well when the antigen in question causes disease and when the studies are being performed in experimental models. An individual is vaccinated with the antigen in question, then challenged with increasing quantities of the pathogenic agent. Thus, in the case of cancer, mice are exposed to a cancer vaccine, then injected later with live cancer cells. If the cancer cells fail to grow, then the animal is immune and one can infer that an immune response was induced. That approach also can be used to quantitate and determine the specificity of the response.
Protection experiments cannot be used to measure anti-cancer immune responses in humans because it would be unethical to inject patients with cancer-causing cells. Since cancer antigens remain to be defined and cell mediated immune responses against cancer involve a complex, poorly understood interplay between several T lymphocyte subpopulations, there is no simple, reliable way to quantitate such responses in vitro. Instead, delayed type hypersensitivity (xe2x80x9cDTWxe2x80x9d) skin testing assays were developed long ago as an alternative in vivo assay for cell mediated immunity. The DTHl reaction takes advantage of the fact that an immune animal or human develops an acquired cellular immune reaction that is characterized by redness and swelling that occurs within 24 to 48 hours following injection of antigen into the site.
Although there are in vitro assays that may be able to be routinely used in the future, the DTH reaction is the only method that has been used so far to measure immune responses against a cancer antigens in humans. See Berd et al., Treatment of Metastic Melanoma with Autologous Tumor Cell Vaccine: Clinical and Immunologic Results in 64 Patients, J. Clin. Oncol. 8:1858-1865 (1990); Hoover and Hanna, Active Immunotherapy in Colorectal Cancer, Semin. Surg. Oncol. 5:436-440 (1989); Lehner et al., Postoperative Active Specific Immunization in Curatively Resected Colorectal Cancer Patients with a Virus-Modified Autologous Tumor Cell Vaccine, Cancer Immunol. Immunother. 32:173-178 (1990). The reasons for this are fourfold. First, although malignant cells are immunogenic, no specific human cancer antigen has yet been identified, characterized, and purified from such cells. Second, DTH responses, like tumor immunity, are mediated locally by a combination of activated Th1 lymphocytes and non-cytotoxic, Th1-like CD8 T lymphocytes. See Cher and Mosmann, Two Types of Murine Helper T Cell Clone. II Delayed-Type Hypersensitivity Is Mediated by TH1 Clones, J. Immunol. 138:3688-3694 (1987); Mody et al., CD8 Cells Play a Critical Role in Delayed Type Hypersensitivity to Intact Cryptococcus Neoformans, J. Immunol. 152:3970-3979 (1994). Third, tumor immunity has been shown to correlate with DTH responses to cancer antigens in animal models. See Puccetti et al., Use of a Skin Test Assay to Determine Tumor-Specific CD8+ T Cell Reactivity, Europ. J. Immunol. 24:1446-1452 (1994); Barth et al., Interferon xcex3 and Tumor Necrosis Factor Have a Role in Tumor Regressions Mediated by Murine CD8+ Tumor-Infiltrating Lymphocytes, J. Exp. Med. 173:647-658 (1991). Finally, currently available in vitro assays for antigen specific T lymphocyte function in humans are technically difficult and unreliable.
Two general approaches have been used in attempts to stimulate the immune system to stop cancer progression. The first approach has been to stimulate innate immune responses. Generally, cancer patients are exposed to a biomodulator, such as Bacillus Calmette Guerin (xe2x80x9cBCGxe2x80x9d), interleukin-2 (xe2x80x9cIL-2xe2x80x9d), tumor necrosis factor (xe2x80x9cTNFxe2x80x9d), or interferon (xe2x80x9cIFNxe2x80x9d), in the hope that non-specifically activated immune cells will inhibit further cancer growth. Unfortunately, with few exceptions, these agents exhibit modest anti-cancer activity, and, like other chemotherapeutic agents, are highly toxic at effective concentrations.
A variation on this innate immunotherapy theme that also has been extensively evaluated has been to take advantage of the fact that biomodulators will increase the anti-cancer activity of immune cells (macrophages, natural killer (xe2x80x9cNKxe2x80x9d) cells, and lymphocytes) in vitro. Exposing lymphocytes to high concentrations of agents such as IL-2 produces lymphokine activated killer (xe2x80x9cLAKxe2x80x9d) cells, which are part of the innate immune system. Although LAK cells are better able to kill cancer cells than normal cells, they exhibit no specificity for cancer antigens. The rationale for therapeutic studies using LAK cells was that, if one could increase the killing capability of lymphocytes, those potentiated lymphocytes would be able to destroy progressing cancers in vivo.
Steven Rosenberg at the National Cancer Institute performed the first human trial of autologous LAK cells in 1985. LAK cells were generated from peripheral blood leukocytes (xe2x80x9cPBLxe2x80x9d) from tumor patients. After culturing the cells in high concentrations of IL-2, the LAK cells were then injected back into the cancer patient. The patients also were exposed to high concentrations (xe2x89xa718 MIU/patient/day) of IL-2 after they had received the LAK cells. See Rosenberg, U.S. Pat. No. 4,690,915. Significant tumor regressions were seen primarily in melanoma and renal cell cancer patients.
Subsequent studies using LAK cells focused on melanoma and renal cancers. In eight different studies, 190 melanoma patients yielded an overall response rate (complete and partial) of 16%. For renal cell cancer, 198 patients from eight different studies reported an overall response rate of 22%. See Chang, Current Status of Adoptive Immunotherapy of Cancer, Crit. Rev. Oncol. Hem. 22:213-228 (1996). However, it is generally believed that the therapeutic effects were due not to the adoptively transferred LAK cells but rather to the high concentrations (xe2x89xa718 MIU/patient/day) of IL-2 that the patients received following infusion of the activated lymphocytes. Subsequent studies in animal models have been unable to document significant in vivo anti-tumor activity for LAK cells by themselves.
A variation on the same innate immunotherapy theme that was also championed by Stephen Rosenberg is the adoptive transfer of tumor infiltrating lymphocytes (xe2x80x9cTILxe2x80x9d). TIL immunotherapy involves using high concentrations (xe2x89xa71000 IU/ml) of IL-2 to stimulate mononuclear cells originally isolated from the inflammatory infiltrate present around solid tumors. The rationale is that TILs may be enriched for tumor specific cytolytic T lymphocytes and NK cells. Researchers theorized that the lymphoid infiltrate within a tumor represents a select population of immune cells which have preferentially migrated to the tumor. Unlike LAK cells, but like activated T lymphocytes, TIL cells are sometimes capable of lysing autologous cancer cells in a fashion that is highly specific and restricted by the major histocompatibility complex (xe2x80x9cMHCxe2x80x9d) class I molecules. Researchers have claimed that TIL immunotherapy is 50-100 times more efficacious than LAK immunotherapy. a Rosenberg, U.S. Pat. No. 5,126,132; Rosenberg et al., Use of Tumor-Infiltrating Lymphocytes and Interleukin-2 in the Immunotherapy of Patients with Metastatic Melanoma, New Engl. J. Med. 319:1676-80 (1988). As with the LAK cell studies, it has been difficult to separate the in vivo effects of TIL from the anti-cancer effects of high dose IL-2.
Another variation on this general approach to generating non-specific effector cells for adoptive transfer to patients is to stimulate PBL from cancer patients with anti-CD3, a non-specific antigen receptor stimulus. See Ochoa et al., U.S. Pat. No. 5,443,983; Ochoa et al., U.S. Pat. No. 5,725,855; Babbit et al., U.S. Pat. No. 5,766,920; Terman, U.S. Pat. No. 5,728,388. The idea was that patients should have circulating cancer antigen specific T lymphocyte precursors whose cancer fighting potential could be increased by stimulating them with anti-CD3 in culture. Such nonspecifically activated T lymphocytes also have no significant anti-tumor effects in vivo, despite the fact that they have been generated from the blood of cancer patients.
The second general immunotherapeutic approach differs from the previous non-specific strategies mainly in that it is designed to induce, then augment, acquired immune responses against the patient""s own cancer cells. The approach is predicated on the well-documented fact that the immune system normally fails to recognize and respond to progressing malignancies, but that it is possible to use vaccination to induce the cancer patient to respond immunologically to molecules expressed by malignant cells but not by normal cells. The basic rationale is that cancer could be successfully treated if one could induce a sufficiently powerful acquired immune response against cancer cell associated antigens.
The most successful strategies that have been tested in this category combine the fact that vaccination induces a protective immune response and that protective immunity can be transferred with activated T lymphocytes. The vaccination portion of this strategy often has been referred to as active specific immunotherapy (xe2x80x9cASIxe2x80x9d). The term xe2x80x9cactivexe2x80x9d is used because vaccination actively induces immune responses. The term xe2x80x9cspecificxe2x80x9d is used because the strategy is designed to induce an immune response against antigens that are expressed by the patient""s own cancer cells. The cell transfer portion of the strategy is generally known as adoptive cellular immunotherapy (xe2x80x9cACIxe2x80x9d). The term xe2x80x9cadoptivexe2x80x9d is used because the strategy involves transferring immune effector cells from one site to another. The term xe2x80x9ccellularxe2x80x9d is used because the strategy involves transferring immune cells.
1. Active Specific Immunotherapy (xe2x80x9cASIxe2x80x9d)
The idea of ASI is well known in the art, and numerous ASI clinical trials have been performed using a wide variety of sources for cancer antigen. There are two basic reasons for taking this approach. Despite widespread controversy about the immunogenicity of particular human cancers, vaccines do induce cancer immunity. There is no theoretical reason why a powerful vaccine could not be therapeutic against cancer. If a vaccine can produce protective immunity that is sufficiently powerful to be therapeutic, it should be relatively simple to add it to the cancer treatment armamentarium.
Several general vaccine strategies are currently being explored. The simplest of those is to vaccinate patients with their own cancer cells. The whole cell approach has been tested for therapeutic efficacy in several human studies. One such study involved treating melanoma patients by vaccinating them with their own chemically altered cancer cells and BCG. See Berd, U.S. Pat. No. 5,290,551; Berd et al., Treatment of Metastatic Melanoma with Autologous Tumor Cell Vaccine: Clinical and Immunologic Results in 64 Patients, J. Clin. Oncol. 8:1858-1865 (1990). A second study involved treating colon cancer patients by vaccinating them with their own cancer cells and BCG. See Hanna, Jr. et al., U.S. Pat. No. 5,484,596; Vermorken et al., Active Specific Immunotherapy for Stage H and Stage III Human Colon Cancer: a Randomized Trial, Lancet 353:345-350 (1999).
Two general facts have become apparent about ASI. The first is that the source of cancer antigen is critical for success. At present, intact, viable cells from the patient""s own cancer provide the best source. The second is that cancer antigen must be combined with an immunologic adjuvant to increase the potency of the vaccine. BCG has been used as the immunologic adjuvant for most human ASI clinical trials. BCG, however, has several disadvantages as an adjuvant, such as its relatively high toxicity and relatively low potency. More recent approaches to increasing the potency of autologous cancer cell vaccines have involved genetically altering the cancer cells to make them more immunogenic. One successful approach involved inserting the gene for the cytokine, granulocyte macrophage colony stimulating factor (xe2x80x9cGM-CSFxe2x80x9d), into tumor cells. See Bonnen et al., U.S. Pat. No. 5,679,356; Dranoff et al., U.S. Pat. No. 5,637,483; Dranoff et al., Vaccination with Irradiated Tumor Cells Engineered to Secrete Murine GM-CSF Stimulates Potent, Specific, Long-Lasting Anti-Tumor Immunity, PNAS (USA) 90:3539-3543 (1993). Very recent observations, however, suggest that simply mixing soluble GM-CSF with autologous cancer cells serves the same purpose. That is, GM-CSF, by itself is a very effective adjuvant.
In sum, the most potent currently available vaccine strategies will induce immune responses in most patients against their own cancer, and multiple vaccination may slow malignant progression. However, ASI by itself does not produce cures either in humans or in animal models.
2. Adoptive Cellular Immunotherapy (xe2x80x9cACIxe2x80x9d)
The idea of ACI also is well known in the art. The first documented experiments involving the cellular transfer of immunity occurred in 1942 when researchers found that DTH to simple chemical compounds could be transferred from sensitized (immune) donors to naxc3xafve (non-immune) recipients with cells from peritoneal exudates. See Landsteiner et al., Experiments on Transfer of Cutaneous Sensitivity to Simple Compounds, Proc. Soc. Exp. Biol. Med. 49:688-690 (1942). This is important for cancer therapy because vaccinating patients with their own cancer cells and an immunological adjuvant will induce strong DTH responses. See Hoover and Hanna, Active Immunotherapy in Colorectal Cancer, Semin. Surg. Oncol. 5:436-440 (1989); Lehner et al., Postoperative Active Specific Immunization in Curatively Resected Colorectal Cancer Patients with a Virus-Modified Autologous Tumor Cell Vaccine, Cancer Immunol. hImunother. 32:173-178 (1990). By 1954, the phrase xe2x80x9cadoptive immunotherapyxe2x80x9d had been coined to describe the acquisition of immunity in a normal subject as a result of transference of immunologically activated lymphoid cells. a Billingham et al., Quantitative Studies on Tissue Transplantation, Proc. R Soc. Exp. Biol. 143:58-80 (1954). The adoptive transfer of lymph node (xe2x80x9cLNxe2x80x9d) cells in mice was reported a year later. a Michison, Studies on the Immunological Response to Foreign Tumor Transplants on the Mouse, J. Exp. Med. 102: 157-177 (1955).
Adoptive transfer of acquired immunity is extremely important because it is a technique that has allowed immunologists to dissect the cellular basis of the immune system. It is not intuitive that adoptive transfer of immune cells would provide a useful immunotherapeutic tool against disease. In fact, while adoptive transfer of immune T lymphocytes transfers protection in the same way that vaccination induces protection, the adoptively transferred lymphocytes by themselves provide little or no therapeutic benefit. They will not reject progressing cancers. Thus, while ACI is well known in the art, it is not obvious that ACI could provide the basis for a potent immunotherapeutic strategy against cancer.
3. Cancer Antigen Immunotherapy (xe2x80x9cCAIxe2x80x9d)
The question researchers next asked was whether ASI and ACI, both of which are protective, could be combined in a way that produces an additive product that is both protective and therapeutic. The immunotherapeutic strategy, however, has to be able to reject preexistent disease. Humans already have cancer when attempts to manipulate the immune system are begun. In fact, even at diagnosis, they usually have more advanced disease than the experimental animals that are the targets for immunotherapy testing.
The rationale for combining ASI and ACI is that while neither vaccination nor adoptive transfer of activated leukocytes from cancer patients are sufficient to make cancers regress, perhaps the two could be synergistic. The immunologic basis for combining the two strategies is that it is essential to induce the patient""s immune system to recognize and respond to antigens that are expressed by malignant cells. Vaccination accomplishes this. Once immune responses have been produced, T lymphocytes could be removed from the immune individual, their number and potency could be increased in the laboratory and they could be returned to the patient where they could travel to sites of cancer growth and reject the progressing cancers. Doing so would produce an overall increase in the number of effector T lymphocytes entering the tumor.
Proof of this principle was established in animal studies in which lymphocytes were removed from immune animals, stimulated with cancer cells and small amounts (xe2x89xa6100 IU/ml) of IL-2 in culture and adoptively transferred to tumor bearing animals. This combinatorial strategy was capable of permanently curing progressing cancer. See Cheever et al., Specific Adoptive Therapy of Murine Leukemia with Cells Secondarily Sensitized in vitro and Expanded in IL-2, Progr. Cancer Res. Ther. 22:127-133 (1982); Chou and Shu, Cellular Interactions and the Role of Interleukin 2 in the Expression and Induction of Immunity Against a Syngeneic Murine Sarcoma, J. Immunol. 139:2103-2109 (1987); Holladay et al., Cytotoxic T lymphocytes, but not Lymphokine Activated Killer Cells, Exhibit Anti-Tumor Activity Against Established Intracerebral Gliomas, J. Neurosurg. 77:757-762 (1992). Those studies clearly demonstrated that therapeutic failures associated with vaccination alone were related to the inability of vaccination to produce high numbers of cancer antigen specific effector T lymphocytes and that the deficiency could be addressed by further activating the T lymphocytes ex vivo in the laboratory and then adoptively transferring the activated cells to tumor bearers. Thus, combining ASI and ACI produced an effective therapeutic strategy.
Later studies demonstrated that immune cancer antigen-specific T lymphocytes could be stimulated to differentiate into effector T lymphocytes using non-specific antigen receptor stimuli such as anti-CD3. The critical step in these studies was that lymphocytes had to be primed with antigen prior to exposure to anti-CD3. See Yoshizawa et al., Specific Adoptive Immunotherapy Mediated by Tumor-Draining Lymph Node Cells Sequentially Activated with Anti-CD3 and IL-2, J. Immunol. 147:729-737 (1991); Saxton et al., Adoptive Transfer of Anti-CD3 Activated CD4+ T Cells Plus Cyclophosphamide and Liposome Encapsulated Interleukin 2 Cure Murine MC-38 and 3LL Tumors and Establish Tumor Specific Immunity, Blood 89:2529-2536 (1997); Shu et al., Stimulation of Tumor-Draining Lymph Node Cells with Superantigenic Staphylococcal Toxins Leads to the Generation of Tumor-Specific Effector T cells, J. Immunol. 152: 1277-88 (1994); Baldwin et al., Ex Vivo Expansion of Tumor Draining Lymph Node Cells Using Compounds which Activate Intracellular Signal Transduction, J. Neuro. Oncol. 32:19-28 (1997). A wide variety of experimental cancers have been shown to be susceptible to these strategies.
The combination of cancer antigen vaccination and adoptive transfer of activated T lymphocytes is known as cancer antigen immunotherapy (xe2x80x9cCAIxe2x80x9d). This combinatorial strategy should be distinguished from other forms of ASI and ACI, particularly those that do not directly involve inducing an acquired immune response against the patient""s own cancer cells.
Chang and his colleagues were the first to report the application of a form of CAI to humans. They vaccinated melanoma and renal cell cancer patients with irradiated autologous cancer cells and BCG. Lymphocytes then were obtained from LNs draining vaccination sites and stinulated in vitro with autologous cancer cells and low-dose IL-2 and infused into patients with concomitant intravenous admninistration of low-dose IL-2. See Chang et al., Clinical Observations on Adoptive Immunotherapy With Vaccine-Primed Lymphocytes Secondarily Sensitized with Tumor In Vitro, Canc. Res. 53:1043-1050 (1993). No clinically significant results were observed.
Holladay and his colleagues performed a similar study in patients with advanced brain cancer. Patients were vaccinated with their own cancer cells and BCG. Peripheral blood T lymphocytes were stimulated with autologous tumor cells and low-dose IL-2 in vitro and reinfused to the patients. S Holladay et al., Autologous Tumor Cell Vaccination Combined With Adoptive Cellular Immunotherapy in Patients with Grade III/IV Astrocytoma, J. Neuro-Oncol. 27:179-189 (1996). Again, no clinically significant results were observed.
More recently, Chang""s group substituted anti-CD3 for tumor cells as the in vitro T lymphocyte stimulus. Se Chang et al., Adoptive Immunotherapy with Vaccine Primed Lymph Node Cells Secondarily Activated with Anti-CD3 and Interleukin-2, J. Clin. Oncol. 15:79-807 (1997). Lymphocytes then were obtained from LNs draining vaccination sites and stimulated in vitro with anti-CD3 and low-dose IL-2 and infused into patients with concomitant intravenous administration of IL-2. Some of the treated cancers regressed, but survival of the patients was not significantly prolonged.
Another group of researchers studied the feasibility, toxicity, and potential therapeutic benefits of another form of CAI in patients with malignant brain tumors. See Plautz et al., Systematic T Cell Adoptive Immunotherapy of Malignant Gliomas, J. Neurosurg. 89:42-51 (1998). Lymphocytes were obtained from LNs draining vaccination sites and stimulated in vitro with staphylococcal enterotoxin A, anti-CD3 and IL-2 and infused into patients with concomitant intravenous administration of IL-2. Again, no clinically significant results were obtained.
From the considerable variety of immunological cancer treatment strategies, it should be clear that there is no intuitively obvious CAI strategy. Nor is there any strategy that has established itself as the best immunologic treatment for human cancer. There is no FDA-approved immunotherapeutic approach to cancer treatment. Even among imnmunotherapists, there is a widespread belief that only a few melanomas and renal cell cancers express some modest immunogenicity and that human malignancies other than melanoma and renal cancer are non-immunogenic and therefore not susceptible to immunotherapy. Accordingly, few of the clinical studies involving immunotherapy have involved the treatment of human cancers other than melanoma or renal cancer, which are relatively uncommon cancers. There also is a widespread belief that, even if human cancers are immunogenic, antigen-specific tolerance and immune suppression would prevent generation of productive immune responses. See Ellem et al., The Labyrinthine Ways of Cancer Immunotherapyxe2x80x94T Cell, Tumor Cell Encounter: xe2x80x9cHow Do I Lose The? Let Me Count the Ways,xe2x80x9d Adv. Canc. Res. 75:203-249 (1998).
The considerable success that has been achieved using CAI in preclinical models predicts that CAI should be at least moderately successful as a treatment for human cancer. Yet, the clinical findings that have been obtained to date in human phase I/II clinical trials do not support such a claim. While the disparity could be attributable to fundamental immunological differences between human and experimental malignancies or the fact that it is not technically possible to implement CAI in humans, this is probably not the explanation. The disparity is most likely not due to conceptual or technical shortcomings in translating CAI from animals to humans, but rather to inappropriate expectations. There was no substantive difference in vaccination strategies nor in the effects of vaccination in experimental animals and humans. Humans and experimental animals both have been successfully vaccinated with whole cancer cells and an immunological adjuvant to induce an immune response against their own malignant cells. Autologous cancer antigen-specific T lymphocytes have been successfully obtained from lymphoid tissue and those T lymphocytes have been successfully activated in vitro in experimental animals and humans. In both cases, those T lymphocytes have exhibited the ability to destroy tumor in vitro. It has been possible to infuse activated T lymphocytes into the bloodstream of experimental animal and human cancer-bearing individuals. The infused T lymphocytes exhibited the ability to produce regression of growing cancers in both experimental animals and humans. Yet, the difference in results has been dramatic. 100% of treated animals were cured in most model systems, while significant anti-cancer effects were observed in only a small proportion of treated cancer patients, and few cures have been documented.
Based on the foregoing, there clearly exists a need to develop a CAI strategy that is effective, non-toxic, and feasible in human cancer patients.
The present invention relates to a cancer antigen immunotherapy strategy for use in treating various types of cancer in humans. More specifically, the present invention is directed to a method of treating cancer comprising the steps of vaccinating a patient with a vaccine comprised of a patient""s own malignancy and an immunologic adjuvant, removing cancer antigen primed PBL from the patient, stimulating primed T lymphocytes to differentiate into effector lymphocytes in vitro, stimulating effector T lymphocytes to proliferate in vitro, and infusing the effector T lymphocytes back into the patient.